Each year, 23,000 women in the United States are diagnosed with ovarian cancer, and although the cancer responds to chemotherapy, most patients experience relapse and die from the disease. However, 15% of patients with stage III disease and 5% to 7% of patients with stage IV disease live 8 years or longer. Are there biologic or quality-of-life (QOL) markers that differentiate these patients who survive long term from those who do not?

This is the question Michael J. Birrer, MD, PhD, of Massachusetts General Hospital Cancer Center, and his coprincipal investigator (PI) Lari Wenzel, PhD, MS, of the UC Irvine School of Medicine, are seeking to answer in a $4 million Department of Defense (DOD) grant, “The Consortium for Long-Term Ovarian Cancer Survival.” Dr. Birrer described the origins of the research and its holistic design, which includes analysis of molecular and genetic markers, as well as QOL factors among long-term survivors.

AC: Your current research came out of a previous grant from the DOD. Can you share some background about the DOD’s funding of ovarian cancer research?

MB: Each year, DOD gives out around $20 million in grants. In 2012, they put out a call for applications for projects in their Ovarian Cancer Research Program— which has been in existence for around 25 years—focusing on the design and implementation of a consortium that would answer this question: “Why do some women with advanced-stage ovarian cancer survive long term, while others do not?” In the application, DOD defined “long-term survivors” as women who have lived 10 years or more after diagnosis. This original research grant came about from advocates who were part of the DOD Ovarian Cancer Integration Panel, asking, “Why am I still alive?” We applied and were awarded the grant along with teams from MD Anderson and University of Southern California.

AC: What was the goal of that original grant?

MB: The goal of that grant was to create a consortium of ovarian cancer researchers and to demonstrate a couple of proof-of-concept projects. Fortunately, it was fairly easy to construct that consortium because we were able to ensconce four separate research centers into the existing infrastructure of the Gynecologic Oncology Group (GOG), which at the time accrued up to 4,000 women per year to trials. Working with GOG gave us a great advantage because they had terrific databases and tumor tissue resources in their bank.

The first project was to demonstrate that the consortium could collect additional tumor tissues, which we did by utilizing the GOG clinical trials structure. We also reached out to survivors through social media and websites. In the second project, we looked at 60 ovarian cancer tissues and analyzed their epigenomic structure, which is methylation, and their immunophenotype to show that we could conduct a preliminary analysis of these molecular endpoints. The final proof-of-principle project was to create a database of QOL patient-reported outcomes among long-term survivors of ovarian cancer. This work was carried out by my co-PI and QOL research expert, Dr. Wenzel.

AC: A major emphasis of the current grant is molecular and genetic analysis of cancer tissue from long-term survivors. What are the goals of that analysis?

MB: The first aim of the study is to look at the molecular and protein features from tumors that were removed at diagnosis from long-term survivors. We’ll be looking at features such as RNA, microRNA, methylation patterns, and proteomic characterization of the tumors from around 300 long-term survivors. We think long-term survival may come from a very strong immune response, so the second aim will be to look at the type of immune cells that infiltrate the tumor, and at the number and quality of the blood vessels to find out more about immune infiltrate in angiogenesis. What’s beautiful about this study is that we can cross-compare immunogenic features with other molecular features. For example, if we find that some tumors have cells with strong immunity, and we think that’s why the patient lives longer, we can see independently if those tumors are immunogenic by looking at the mRNA sequences or the microRNA patterns.

For aim three, we’ll be looking at the 25% of patients with ovarian cancer who are diagnosed at an early stage, that is stage I or II. At least 50% to 60% of these patients will never have a recurrence; however, what’s concerning is that all of these patients are treated with six cycles of chemotherapy because we can’t identify those who will recur from those who will not. Our goal is to try to develop an Oncotype DX-type test for women with early-stage ovarian cancer. Once we have this, at the time of surgery we can tell women their risk of recurrence, allowing them to decide ahead of time whether they want adjuvant chemotherapy.

Aim four looks not at the tumor specifically, but at the genomic constitution of the patient, in order to ask: Does long-term survival have something to do with a genomic profile that makes a patient’s immune system more active, or makes their blood vessels form a certain way so that the tumors don’t grow fast? For this research question, we’ll also be looking at the ways environmentally induced stress impacts patient survival; in other words, do patients who are stressed do more poorly than patients who are not stressed? We’ll be looking at QOL surveys as well as peripheral blood, such as corticosteroids or epinephrine, as surrogates to stress.

AC: Part of what makes this study unique is the integration of QOL variables. What role will those play in the research?

MB: For aim five and six of the study, Dr. Wenzel is going to study the presurgery QOL and psychosocial components for long-term survivors to see if there’s a predictive signature that separates patients who are going to do well from those who will not do as well. We’ll also be looking at the QOL among women who are 10 years out, and asking how many of them are left with a paclitaxel-induced neuropathy that causes problems in day-to-day life. We’ll also be studying long-term survivors’ sexual health, which currently remains an unknown quantity. The great advantage of a study like this is that we can talk to 300 survivors of ovarian cancer. Outside of a project like this, there’s no way to get that kind of data, and I’m grateful to have this opportunity.